Hepatitis C virus (HCV) is an important human pathogen that primarily infects human hepatocytes and causes many chronic liver diseases. Unfortunately, there is no prophylactic vaccine currently available, and combination therapy with pegylated interferon (IFN)-α and ribavirin is only effective in 40-80% of patients and has severe side effects that results in poor patient compliance. Therefore, new antiviral drugs are urgently needed to treat HCV infection in combination with current therapies.
Research on HCV was revolutionized by the advent of the Japanese fulminant HCV strain (JFH-1) that can be cultivated in cell culture (HCVcc) and hence permits the study of the entire viral life cycle (see, for example, Lindenbach et al., Science 2005; 309:623-626). HCV entry requires at least four cellular membrane proteins, including CD81 (Pileri et al, Science 1998; 282:938-941), scavenger receptor BI (SR-BI)(Scarselli et al., Embo J 2002; 21:5017-5025), claudin-1 (CLDN1)(Evans et al., Nature 2007; 446:801-805), and occludin (OCLN) (Liu, J Virol 2009; 83:2011-2014; Ploss et al., Nature 2009; 457:882-886). Remarkably, another host factor, human apolipoprotein E (apoE), appears to be assembled into infectious virions and plays a crucial role in conferring virus infectivity (see, for example, Chang et al., J Virol 2007; 81:13783-13793). The 299-residue apoE is a main component of lipoproteins in plasma and participates in lipid transport via its ability to bind to multiple cell surface receptors, including low density lipoprotein receptor (LDLR), apolipoprotein E receptor 2 (apoER2), very low density lipoprotein receptor (VLDLR), SR-BI, low density lipoprotein receptor-related protein 1 (LRP1), and heparan sulfate proteoglycan (HSPG) (Bu, Nat Rev Neurosci 2009; 10:333-344), some of which have been implicated in HCV entry (reviewed in Popescu and Dubuisson, Biol Cell 2009; 102:63-74).
Disclosed herein are novel peptide inhibitors of HCV infection derived from human apoE that block HCV binding to cell surface.